Mutation rates in man

Question 1

What are the different levels of mutation?

Answer 1

Chromosomal - aneuploidy

Genomic regional - translocational/inversion

Whole gene level - whole gene deletion/duplication

Nucleotide level - change, deletion, duplication, change of nucleotide sequence

Question 2

What are germline mutations?

Answer 2

Can be inherited by offspring

Question 3

What are somatic mutations?

Answer 3

Postzygotic mutation

these are not inherited

Question 4

When are mutations heritable in all situations?

Answer 4

Heritable at the cellular level

Question 5

Do mutations occur in hotspots and what are the main mechanisms of molecular hotspots?

Answer 5

Yes:

Transitions of CpG dinucleotides
Slipped mispairing at DNA replication

Question 6

What is the CpG mechanism hotspot?

Answer 6

Transitions at CpG dinucleotides

Methylation of cytosine ( to 5- methyl cytosine) next to a guanine is the major form of DNA modification

Question 7

What is the slipped mispairing hotspot?

Answer 7

Slipped mispairing at DNA replication

• changes in repeat number in a microsatellite repeat
• offspring has an allele of a different size than either parent
  can occur at increased frequency due to defective mismatch repair
• mutator phenotype, seen at multiple loci
  -e.g. colon cancer

Question 8

What did Weinberg notice about achondroplasia and why was this?

Answer 8

That it is most often the last born children with the disease which is supposedly due to there being a higher mutation rate in older men so more sperm mutations.

Question 9

Does the type and frequency of mutation differ between males and females?

Answer 9

Yes since many mutations occurring on the X chromosome are inactivated in females.

Question 10

What is Achondroplasia and where does this mutation occur?

Answer 10

ACH is a fully penetrant dominant disease (dwarfism)

Occurs at the CpG dinucleotide of methylcytosine to thymine

Question 11

What do these six conditions have in common:
Crouzon Pfeiffers syndromes
MEN 2A
 MEN2B
Apert syndrome
Achondroplasia

Answer 11

All of paternal origin
All single base mutations
6 conditions involve 3 genes.

Question 12

What is the cause of high male mutation rate?

Answer 12

many more cell divisions in male gametogenesis than females.

DNA replication/repair is the majority of mutations so expect a higher rate.

predicted increase of genetic load with age.

predicted increased frequency of paternally derived mutations.

Question 13

What does a greater number of replications in males vs female gametogenesis predict?

Answer 13

An increased frequency of paternally derived mutations

An increased genetic load with age

Question 14

What does accurate DNA sequencing of the whole human genome allow us to do?

Answer 14

Compare the mutations in both parents with offspring

Therefore get an estimate of new mutations produced in each generation.

Question 15

What does every additional year of paternal age result in, in terms of mutations in the offspring?

Answer 15

per every additional year, there are on average an extra 2 mutations in the offspring

Question 16

How many mutations are transmitted in maternal figures?

Answer 16

Always 15 mutations in offspring regardless of age

Question 17

Is there an acceleration rate of mutation with paternal age?

Answer 17

Yes

Question 18

Why is there an accelerating rate of mutation?

Answer 18

Reduced fidelity of DNA repair and replication mechanisms

Cell death in old age might be compensated by increased number of cell divisions

Accumulation of mutagens

Question 19

What are the exceptions to the paternal age effect?

Answer 19

Neurofibromatosis I
Duchenne Muscular Dystrophy

Both are extremely large genes (55-59 exons) and hence mutation rates are very high as there are many deletions.

Question 20

Why are deletions common in large genes?

Answer 20

They have the space to take them out. Such deletions in smaller genes would be lethal and therefore not observed.

Question 21

Why are small chromosomal deletions not age dependent?

Answer 21

They occur through a different mechanism.

Rate of occurrence of deletions is higher in females than males

Question 22

What are special about these loci:

FGFR2, FGFR3 and RET ?

Answer 22

Mutation exclusively paternal
Unique to spermatogenesis
Paternal age effect is observed

Mutations are all gain of function and confer a selective advantage.

Question 23

What other mutation type shows a sex bias?

Answer 23

Trinucleotide repeats:

Eg. Huntingtons disease (CAG 11-34 repeats)

Paternally derive loci have more repeats than maternally derived ones

Question 24

Is mutation rate determined by evolution?

Answer 24

Mutation rates as a balance between benefit and liability:
too low leads to a species that is not adaptive
- too high leads to a species in which there is disease

Question 25

What do mutation rates reflect?

Answer 25

Replication error - major contributor

Copying, proofreading, repair tuned

Question 26

What is the median mutation rate?

Answer 26

1 in 1000000 per locus per generation.

Question 27

What is the crow hypothesis?

Answer 27

likelihood of removal of a zygote increases with number of deleterious mutations.

Question 28

How does sexual reproduction mitigate the effect of the high mutation rate?

Answer 28

by eliminating harmful mutations.